The present invention relates to processes and intermediates for preparing compounds that are useful in the treatment of hyperproliferative disorders, such as cancers, in mammals.
U.S. Pat. No. 5,747,498, which issued on May 5, 1998 and is incorporated herein by reference in its entirety, refers to a novel series of quinazoline derivatives, including [6,7-bis(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride, which are inhibitors of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), and are therefore useful for the treatment of proliferative disorders, such as cancers, in humans. United States provisional patent application 60/083,441 entitled xe2x80x9cN-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine Mesylate Anhydrate And Monohydrate,xe2x80x9d filed Apr. 29, 1998, with named inventors T. Norris, D. Santafianos, D. J. M. Allen, R. M. Shanker, and J. W. Raggon, which is incorporated herein by reference in its entirety, refers to N-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine mesylate anhydrate and hydrate forms which possess the same anti-cancer utility as the corresponding hydrochloride salt referred to above. The present invention relates to methods and intermediates for preparing anti-cancer compounds referred to in the United States patent and patent application referred to above.
The present invention relates to a process for preparing compounds of the formula 
and pharmaceutically acceptable salts and solvates of said compounds, wherein:
R1 and R2 are each independently selected from C1-C10 alkyl and C1-C10 alkoxy wherein said alkyl and alkoxy are optionally substituted by up to 2 substituents independently selected from hydroxy and C1-C6 alkoxy;
R15 is H, C1-C10 alkyl, or xe2x80x94(CH2)q(C6-C10 aryl), wherein q is an integer from 0 to 4;
which comprises treating a compound of the formula 2 
wherein R15, R1 and R2 are as defined above, and G is a blocking group from xe2x80x94C(OH)R3R4 and xe2x80x94SiR3R4R5;
with either (a) an alkali-metal or alkaline-metal hydroxide in a solvent comprising a hydroxy-substituted C1-C10 alkyl where G is xe2x80x94C(OH)R3R4, or (b) a tetra-(C1-C6 alkyl)-ammonium fluoride compound in an aprotic solvent where G is xe2x80x94SiR3R4R5.
In a preferred embodiment, where G is xe2x80x94C(OH)R3R4, said solvent is a secondary alcohol, such as butan-2-ol or isopropanol, and said alkali-metal or alkaline-metal hydroxide is selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, most preferably sodium hydroxide.
In another preferred embodiment, where G is xe2x80x94SiR3R4R5, said tetra-(C1-C6 alkyl)-ammonium fluoride compound is tetra-(n-butyl)-ammonium fluoride and said aprotic solvent solvent is selected from tetrahydrofuran (THF), diethyl ether, dimethoxyethane (DME), toluene, dichloromethane, chloroform, and mixtures of two or more of the foregoing solvents, most prefereably THF.
The present invention also relates to the preparation of a compound of formula 2, as described above, which comprises treating a compound of the formula 3 
wherein R1 and R2 are as defined above, with a compound of the formula 4 
wherein G and R 15 are as defined for said compound of formula 2.
In a preferred embodiment of the above method, the compound of formula 3 is treated with the compound of formula 4 in an organic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), THF, acetonitrile (MeCN), or a mixture of two or more of the foregoing solvents, more preferably acetonitrile.
The present invention also relates to the preparation of the compound of formula 3, as defined above, which comprises treating a compound of formula 5 
with thionyl chloride in anhydrous dichloromethane.
In a preferred embodiment of each of the reactions described above, R1 and R2 are both 2-methoxyethoxy and R15 is H.
The present invention also relates to the preparation of compounds of the formula 6 and 7 
and the pharmaceutically acceptable salts and solvates thereof, wherein R15 is as defined above, R6 is C1-C10 alkyl or xe2x80x94(CH2)mO(CH2)nCH3;
R7 is C1-C10 alkyl or xe2x80x94(C1-C6 alkyl)(C6-C10 aryl) wherein the foregoing R7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6 alkyl)sulfonyl, C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryloxy and C6-C10 arylsulfonyl;
each m is independently an integer from 1 to 6, and n is an integer from 0 to 3;
which comprises treating a compound of the formula 8 
wherein G1 is xe2x80x94C(OH)R3R4, and R15, R6, R3 and R4 are as defined above, with a primary or secondary alcohol of the formula R7xe2x80x94OH wherein R7 is as defined above, in the presence of an alkali-metal or alkaline-metal hydroxide, such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, most preferably sodium hydroxide.
In a preferred embodiment of the above reaction, R6 is 2-methoxyethoxy and said alcohol of formula R7xe2x80x94OH is preferably a secondary alcohol.
The present invention also relates to a method of preparing compounds of the formula 
and the pharmaceutically acceptable salts and solvates thereof, wherein R15, R6 and R7 are as defined above;
R8, R9 and R10 are each independently selected from H, C1-C10 alkyl, halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, xe2x80x94OR11, xe2x80x94C(O)R11, xe2x80x94C(O)OR11, xe2x80x94NR12C(O)OR14, xe2x80x94OC(O)R11, xe2x80x94NR12SO2R14, xe2x80x94SO2NR11R12, xe2x80x94NR12C(O)R11, xe2x80x94C(O)NR11R12, xe2x80x94NR11R12, xe2x80x94S(O)j(CH2)q(C6-C10 aryl), xe2x80x94S(O)j(C1-C6 alkyl), wherein j is an integer from 0 to 2, xe2x80x94(CH2)q(C6-C10 aryl), xe2x80x94O(CH2)q(C6-C10 aryl), xe2x80x94NR12(CH2)q(C6-C10 aryl), and xe2x80x94(CH2)q(4-10 membered heterocyclic), wherein q is an integer from 0 to 4; said alkyl group optionally contains 1 or 2 hetero moieties selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer from 0 to 2, and xe2x80x94N(R12)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, aryl and heterocyclic groups are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, xe2x80x94NR12SO2R14, xe2x80x94SO2NR11R12, xe2x80x94C(O)R11, xe2x80x94C(O)OR11, xe2x80x94OC(O)R11, xe2x80x94NR12C(O)OR14, xe2x80x94NR12C(O)R11, xe2x80x94C(O)NR11R12, xe2x80x94NR11R12, xe2x80x94OR11, C1-C10 alkyl, xe2x80x94(CH2)q(C6-C10 aryl), and xe2x80x94(CH2)q(4-10 membered heterocyclic), wherein q is an integer ranging from 0 to 4;
each R11 is independently selected from H, C1-C10 alkyl, xe2x80x94(CH2)q(C6-C10 aryl), and xe2x80x94(CH2)q(4-10 membered heterocyclic), wherein q is an integer ranging from 0 to 4; said alkyl group optionally includes 1 or 2 hetero moieties selected from O, xe2x80x94S(O)jxe2x80x94 wherein j is an integer from 0 to 2, and xe2x80x94N(R12)xe2x80x94 with the proviso that two O atoms, two S atoms, or an O and S atom are not attached directly to each other; said aryl and heterocyclic R11 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R11 substituents, except H, are optionally substituted by 1 to 5 substituents independently selected from halo, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, xe2x80x94C(O)R12, xe2x80x94C(O)OR12, xe2x80x94OC(O)R12, xe2x80x94NR12C(O)R13, xe2x80x94C(O)NR12R13, xe2x80x94NR12R13, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
each R12 and R13 is independently H or C1-C6 alkyl; and,
R14 is selected from the substituents provided in the definition of R11 except R14 is not H;
which comprises treating a compound of the formula 10 
wherein R11, R6, R8, R9 and R10 are as defined above; with a primary or secondary alcohol of the formula R7xe2x80x94OH wherein R7 is as defined above, preferably a primary alcohol, in the presence of an alkali-metal or alkaline-metal hydroxide, such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, most preferably sodium hydroxide.
The above compounds of formulas 1, 6, 7 and 9 are useful in the treatment of hyperproliferative disorders, such as cancers, in mammals.
The present invention also relates to intermediates of the formula 2 as described above with reference to the preparation of the compounds of formula 1.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties, or a combination of the foregoing moieties. It is understood that for said alkyl group to include cyclic moieties at least three carbon atoms are required in said alkyl group.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term xe2x80x9c4-10 membered heterocyclicxe2x80x9d, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 4-10 atoms in its ring system. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 4 membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyl and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds prepared according to the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds prepared according to the present invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
Those compounds prepared according to the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
The compounds prepared according to the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers and stereoisomers of the compounds prepared according to the present invention, and mixtures thereof. The compounds of formula 1 may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The subject invention also includes isotopically-labelled compounds prepared according to the present invention, and the pharmaceutically acceptable salts thereof, which are identical to those recited in Formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, and 36Cl, respectively. Compounds prepared according to the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula 1 of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. 
The methods of the present invention may be described through reference to Schemes 1 to 3 above. In the reactions described below, all reactions are conducted at atmospheric pressure and room temperature (about 20-25xc2x0 C.) unless other conditions are specified. Further, unless otherwise noted, substituents R1-R10, R15 G and G1 are as described above.
In Scheme 1, compounds of formula 1 may be prepared by first treating starting compound of formula 5, which may be prepared according to methods familiar to those skilled in the art, with thionyl chloride in anhydrous dichloromethane at reflux temperature (about 38-42xc2x0 C. at atmospheric pressure) to obtain the compound of formula 3. The compound of formula 2 may be obtained by treating the compound of formula 3 with the compound of formula 4 in an organic solvent, such as DMF, DMSO, THF, MeCN, or a mixture of two or more of the foregoing solvents, preferably MeCN, at a temperature ranging from 50xc2x0 C. to reflux, preferably reflux. The foregoing acronyms are as defined in the Summary of the Invention, referred to above. The compound of formula 1 may be prepared by treating the compound of formula 2 with an alkali-metal or alkaline-metal hydroxide in a solvent comprising C1-C10 alkyl substituted by at least one hydroxy group where G is xe2x80x94C(OH)R3R4, or with a tetra-(C1-C6 alkyl)-ammonium fluoride compound in an aprotic solvent where G is xe2x80x94SiR3R4R5. Where G is xe2x80x94C(OH)R3R4, the solvent is preferably a secondary alcohol, such as butan-2-ol or isopropanol, said alkali-metal or alkaline-metal hydroxide may be selected from sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide and potassium hydroxide, preferably sodium hydroxide, and the reaction is preferably run at a temperature ranging from about 100xc2x0 C. to about 150xc2x0 C. Where G is xe2x80x94SiR3R4R5, the tetra-(C1-C6 alkyl)-ammonium fluoride compound is preferably tetra-(n-butyl)-ammonium fluoride, the aprotic solvent may be selected from THF, diethyl ether, DME, toluene, dichloromethane, chloroform, and a mixture of two or more of the foregoing solvents, preferably THF, and the reaction is preferably conducted a temperature ranging from about room temperature to about 70xc2x0 C. The anti-cancer compounds of formula 1 may be converted to pharmaceutically acceptable salts as described below.
In Scheme 2, anti-cancer compounds of formulas 6 and 7 may be prepared by treating intermediate of formula 8 with a primary or secondary alcohol of formula R7xe2x80x94OH, wherein R7 is as defined above, in the presence of an alkali-metal or alkaline-metal hydroxide such as sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide or potassium hydroxide, preferably sodium hydroxide, at a temperature ranging from about 100xc2x0 C. to about 150xc2x0 C. Use of a secondary alcohol of formula R7xe2x80x94OH will minimize conversion to the asymmetric analogue of formula 7, while use of a primary alcohol of formula R7xe2x80x94OH will increase the relative concentration of the asymmetric analogue of formula 7. Thus, depending on the analogue that is preferred, a secondary or primary alcohol may be preferred. The compounds of formula 6 and 7 may be separated by various methods, such as chromatography, which are familiar to those skilled in the art. The compounds of formula 6 and 7 may be converted to pharmaceutically acceptable salts as described below.
In Scheme 3, compounds of formula 9 may be prepared by treating compounds of formula 10 with a primary or secondary alcohol of formula R7xe2x80x94OH as described above in reference to Scheme 2. Since the goal of the reaction of Scheme 3 is the preparation of the asymmetric analogue, the use of primary alcohol of formula R7xe2x80x94OH is preferred. The compounds of formula 9 may be converted to pharmaceutically acceptable salts as described below.
Certain compounds prepared according to the present invention referred to above may have asymmetric carbon atoms. Compounds having a mixture of isomers at one or more centers will exist as diastereomeric mixtures, which can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. All such isomers, including diastereomer mixtures, are considered as part of the invention.
The compounds referred to above that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to mammals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
Those compounds referred to above that are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired alkali metal alkoxide or metal hydroxide, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide or metal hydroxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
The Examples provided below further exemplify the methods and intermediates of the present invention, although it is understood that the scope of the present invention is not limited by the following examples.